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US20160311805A1 - Anti-estrogenic compounds - Google Patents

Anti-estrogenic compounds Download PDF

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Publication number
US20160311805A1
US20160311805A1 US15/135,840 US201615135840A US2016311805A1 US 20160311805 A1 US20160311805 A1 US 20160311805A1 US 201615135840 A US201615135840 A US 201615135840A US 2016311805 A1 US2016311805 A1 US 2016311805A1
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United States
Prior art keywords
formula
compound
equiv
methyl
phenyl
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Abandoned
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US15/135,840
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Inventor
Peter J. Kushner
David C. Myles
Cyrus L. Harmon
Leslie Carol HODGES GALLAGHER
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Pfizer Corp SRL
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Pfizer Corp SRL
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Priority to US15/135,840 priority Critical patent/US20160311805A1/en
Publication of US20160311805A1 publication Critical patent/US20160311805A1/en
Priority to US15/676,400 priority patent/US20170362210A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the field of pharmaceuticals, and in particular, to novel 2H-chromene compounds, salts, and prodrugs thereof.
  • the present invention also relates to the medical uses of the compounds, including as estrogen receptor modulators, and for the treatment of medical conditions that would benefit from an anti-estrogenic drug, and pharmaceutical salts and compositions thereof.
  • Estrogen receptor modulators are a class of compounds that act on the estrogen receptor. These compounds can be pure agonists (mimicking estrogen), pure antagonists, or mixed agonist-antagonists (sometimes referred to as Selective Estrogen Receptor Modulators (SERMs)). For example, estradiol is a pure agonist, fulvestrant is a complete antagonist, and tamoxifen and raloxifene are SERMs.
  • ER estrogen receptors
  • Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • fulvestrant is substantially superior to the aromatase inhibitor anastrozole in treating metastatic breast cancer (Robertson et al. J Clin Oncol (2009) 27(27):4530-5).
  • the degree of anti-estrogenicity is often assayed by exposing female, immature (preferably ovariectomized) rodents to test doses of the compound both in the absence (agonist mode) and presence (antagonist mode) of estrogen.
  • Tamoxifen and other partial anti-estrogens stimulate uterine weight gain in the agonist mode and only partly block estrogen-driven uterine weight gain in the antagonist mode.
  • Fulvestrant and other complete anti-estrogens do not stimulate uterine weight gain in the agonist mode and completely block estrogen-driven weight gain in the antagonist mode.
  • the induction of estrogen-regulated alkaline phosphatase expression in human uterine cancer cell growth in culture can be used to distinguish partial and complete anti-estrogenicity and correlates well with the rodent weight gain assay.
  • Tamoxifen and fulvestrant both inhibit cultured human breast cancer cell proliferation provoked by estrogen. However, fulvestrant more fully inhibits the proliferation when provoked with growth factors, especially of the insulin/insulin-like growth factor family.
  • growth-factor driven breast cancer cell proliferation and the effect on uterine weight provide two assays which can distinguish between complete and partial anti-estrogens.
  • SELDs Selective Estrogen Receptor Degraders
  • tamoxifen binding stabilizes the estrogen receptor
  • fulvestrant and chemically related antiestrogens such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor.
  • the ability to induce degradation of the receptor is a factor that differentiates the behavior of tamoxifen and fulvestrant and may be desirable in a drug to treat breast cancer.
  • Fulvestrant incorporates a core of 17-beta estradiol.
  • the estradiol core blocks oral absorption and the long flexible aliphatic side chain makes the drug very insoluble which worsens the problem.
  • Fulvestrant must be injected because of its poor oral bioavailability.
  • Two 5 ml intramuscular depot injections, one into each buttock, must be administered monthly by a health professional. Furthermore, it is unclear whether these two injections provide sufficient drug exposure for optimal action. The drug does not seem to work in pre-menopausal women.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, m, n, p and q are as defined hereinabove.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and m are as defined hereinabove.
  • X is CH 2 or O. In another embodiment, X is NH or N—(C 1 -C 4 alkyl). In another embodiment, X is CH 2 or S. In another embodiment, X is O, and in a still further embodiment, X is CH 2 , and in another embodiment, X is S.
  • n is 0. In another embodiment, m is 1.
  • R 1 is —C((Y 1 )(Y 2 )) m —CH 3 , where m and Y 1 and Y 2 are as defined herein. In a further embodiment, R 1 is —CH 2 —CH 3 . In another embodiment, R 1 is (CH 2 ) m —C((Y 3 )(Y 4 )(Y 5 )), wherein m, Y 3 , Y 4 and Y 5 are as defined herein. In another embodiment, one or more of the hydrogen atoms attached to a carbon atom is replaced by fluorine.
  • R 1 is —(CH 2 ) m —CH 2 F
  • R 1 is —(CH 2 ) m —CHF 2
  • R 1 is —(CH 2 ) m —CF 3
  • R 1 is CHF—CH 3 , CF 2 CH 3 , CH 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CHFCH 2 F, CHFCHF 2 , CHFCF 3 , CF 2 CH 3 , CF 2 CH 2 F, CF 2 CHF 2 , CF 2 CF 3 , CH 2 F, CHF 2 , CH 3 , or CF 3 .
  • R 1 is CH 2 F, CHF 2 , CH 3 , or CF 3 .
  • —C((Y 3 )(Y 4 )(Y 5 )) is CH 3 or CF 3 .
  • R 2 is hydrogen, halogen, such as F, Cl or Br, cyano or hydroxy, while in another embodiment, R 2 is hydrogen, halogen or hydroxy. In a further embodiment, R 2 is hydrogen or hydroxy. In an embodiment, R 2 is hydrogen. In another embodiment, R 2 is hydroxy.
  • R 3 is hydrogen, F, Br, Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, —CH 2 F, —CHF 2 , or —CF 3 .
  • R 3 is hydrogen or C 1 -C 4 alkyl.
  • R 3 is methyl, isopropyl or hydrogen.
  • R 3 is hydrogen or isopropyl.
  • R 3 is methyl.
  • R 3 is hydrogen.
  • R 4 is hydroxy and R 5 is hydrogen or halogen, for example, bromine, fluorine or iodine. In another embodiment, R 5 is hydroxy, and R 4 is hydrogen or halogen, for example, bromine, fluorine or iodine. In another embodiment, R 4 is hydroxy and R 5 is hydrogen, while in another embodiment, R 5 is hydroxy and R 4 is hydrogen. In another embodiment, R 4 is hydroxy. In another embodiment, R 5 is hydrogen or halogen. In another embodiment, R 5 is hydrogen.
  • R 6 is hydrogen or bromine, fluorine or iodine, and in another embodiment, is hydrogen or fluorine or chlorine, and in another embodiment, is hydrogen or fluorine, and in still further embodiment, is hydrogen and in still another embodiment, is fluorine.
  • R 7 is hydrogen or bromine, fluorine or iodine, and in another embodiment, is hydrogen or fluorine or chlorine, and in another embodiment, is hydrogen or fluorine, and in still further embodiment, is hydrogen and in still another embodiment, is fluorine.
  • R 6 is hydrogen, R 7 is hydrogen or fluorine, and R 8 is hydrogen. In another embodiment, R 6 is hydrogen or fluorine, R 7 is fluorine, and R 8 is hydrogen. In an embodiment, R 6 is hydrogen and R 7 is hydrogen or fluorine. In another embodiment, R 6 is hydrogen or fluorine and R 7 is fluorine. In an embodiment, R 6 is hydrogen, R 7 is hydrogen, and R 8 is hydrogen.
  • X is CH 2 , R 1 is CH 2 —CH 3 or CH 2 —CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen or fluorine, R 7 is hydrogen or fluorine and R 8 is hydrogen.
  • X is CH 2 , R 1 is CH 2 —CH 3 or CH 2 —CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen or fluorine, and R 7 is hydrogen or fluorine.
  • X is O
  • R 1 is CH 2 —CH 3 or CH 2 —CF 3
  • R 2 is hydroxy
  • R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen
  • R 6 is hydrogen
  • R 7 is hydrogen or fluorine
  • R 8 is hydrogen.
  • X is O
  • R 1 is CH 2 —CH 3 or CH 2 —CF 3
  • R 2 is hydroxy
  • R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen
  • R 6 is hydrogen and R 7 is hydrogen or fluorine.
  • X is CH 2 , R 1 is CH 3 or CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen or fluorine, R 7 is hydrogen or fluorine and R 8 is hydrogen.
  • X is CH 2 , R 1 is CH 3 or CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen or fluorine, and R 7 is hydrogen or fluorine.
  • X is O, R 1 is CH 3 or CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen, R 7 is hydrogen or fluorine, and R 8 is hydrogen.
  • X is O, R 1 is CH 3 or CF 3 , R 2 is hydroxy, R 3 is hydrogen, one of R 4 and R 5 is hydroxy and the other is hydrogen, R 6 is hydrogen and R 7 is hydrogen or fluorine.
  • Embodiments described herein relate to a compound of Formula I wherein the aryl moiety substituted by R 2 , R 3 and R 8 is selected from:
  • a compound is selected from the group consisting of
  • a compound is selected from the group consisting of
  • a compound is selected from the group consisting of
  • a compound of the present invention is in the S configuration at the asymmetric carbon, as described below.
  • Embodiments relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the embodiments of Formula I, Formula IA, Formula II, or Formula IIA, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Embodiments relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the embodiments of Formula I, Formula IA, Formula II, or Formula IIA, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiments relate to a method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient an amount of a compound of any of the embodiments of Formula I, Formula IA, Formula II, or Formula IIA, or a pharmaceutically acceptable salt thereof
  • Embodiments related to the method of treating a disorder wherein the disorder is selected from the group consisting of ovarian, endometrial, vaginal cancer, endometriosis or lung cancer.
  • Embodiments related to the method of treating a disorder mediated by the estrogen receptor further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
  • Embodiments related to the method of treating a disorder mediated by the estrogen receptor further comprising administering the compound in combination or alternation with estrogen or a partial estrogen receptor antagonist for the treatment of a postmenopausal disorder.
  • the compound of the present specification of Formula I, IA, II or IIA can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide, and optionally in a pharmaceutically acceptable composition to treat a disorder that is modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound.
  • the compound of Formula I, Formula IA, Formula II or Formula IIA is provided as a prodrug, for example, an ester, ether, amide, carbonate or phosphate.
  • the compound of Formula I, Formula IA, Formula II or Formula IIA has at least one isotopic substitution, and in particular, for example, at least one substitution of deuterium for hydrogen.
  • deuterium in place of a hydrogen at one or more of the positions of the Formulas are provided.
  • disorders that can be treated with the compounds described herein include, but are not limited to, locally advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both, and to early (surgically treatable) estrogen or progesterone receptor positive breast cancer, for treatment of which the compounds may be administered prior to surgery or following surgery to decrease the risk of recurrence.
  • the described compounds or their pharmaceutically acceptable salts or compositions are therefore useful as adjunctive therapy after or instead of chemotherapy, radiation or surgery. They are also useful for the prevention of breast cancer in women at high risk or for treatment of other cancers and other overgrowth diseases of estrogen-receptive tissue, such as the female reproductive tract including ovarian, endometrial, vaginal cancer and endometriosis.
  • the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
  • “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • C 1 -C 4 alkyl refers to an alkyl group which contains 1-4 carbon atoms.
  • the alkyl group may be a straight-chained, branched or cyclic. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, and cyclobutyl.
  • halogen refers to fluorine, chlorine, bromine or iodine, and in particular, fluorine.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic, and may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropy
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1): 1-79 (January '77).
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Solidvate refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline or liquid form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • a “subject” or “patient” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)).
  • the subject can be a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pig, horse, sheep, goat, rodent, cat, and/or dog.
  • primates e.g., cynomolgus monkeys, rhesus monkeys
  • cattle, pig, horse, sheep, goat, rodent, cat, and/or dog Unless otherwise indicated, the term subject in a claim refers to a human.
  • the term “enantiomerically pure” or “pure enantiomer” denotes that the compound in the specific enantiomer, whether it be the R isomer or the S isomer, comprises more than 95% by weight. In alternative embodiments, the term may refer to more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. The weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “diastereomerically pure” or “pure diastereomer” denotes that the compound in the specific diastereomer, comprises approximately 95% or more by weight.
  • the term may refer to more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the diastereomer.
  • the weights are based upon total weight of all stereoisomers of the compound.
  • the term “enantiomerically pure R-compound” refers to at least about 95% by weight R-compound and at most about 5% by weight S-compound. In alternative embodiments, the term can refer to at least about 99% by weight R-compound and at most about 1% by weight S-compound or at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
  • the term “enantiomerically pure 5-compound” or “S-compound” refers to at least about 95% by weight S-compound and at most about 5% by weight R-compound. In alternative embodiments, the term can refer to at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.
  • terapéuticaally effective amount means an amount of the composition's active component sufficient to treat a particular condition.
  • the present invention includes the compounds of Formulas I, IA, II or IIA and the use of compounds with desired isotopic substitutions of atoms, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • a preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
  • the deuterium can be bound in a location of bond breakage during metabolism (an ⁇ -deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
  • substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond.
  • the hydrogen atom can be any isotope of hydrogen, including protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).
  • isotopically-labeled refers to an analog that is a “deuterated analog”, a “ 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
  • deuterated analog means a compound described herein, whereby an H-isotope, i.e., hydrogen/protium ( 1 H), is substituted by an H-isotope, i.e., deuterium ( 2 H).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location.
  • the compounds of the Formulae described herein are substantially pure.
  • substantially pure it is meant for example that the compounds of Formula I, IA, II and Formula IIA are at least about 80% by weight pure.
  • the compound of Formula I, IA, II and Formula IIA is at least about 85% by weight pure, while in another embodiment, it is at least about 90% by weight pure.
  • the term “substantially pure” means that the compound of Formula II and Formula IIA is at least about 95% pure by weight. In another embodiment, it is at least about 97% pure by weight, and in another embodiment, it is at least about 98% and in still another embodiment, it is at least about 99% pure by weight. Unless otherwise indicated, the term substantially pure means at least about 90% by weight.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III include stereoisomers thereof, including, without limitation, enantiomers, diastereomers and racemic mixtures thereof, unless the chemical structure depicts a certain stereo configuration. In that case, the corresponding enantiomer, diastereomer or racemic mixture may be used in an alternative embodiment.
  • the carbon atom at the 2-position of the chromene backbone of the compounds of Formula I or Formula IA which is bonded to the phenyl group is an asymmetric carbon; thus, it may exist in either the R or S configuration.
  • the present disclosure includes the R-isomer at the 2-position of the chromene, the S-isomer at the 2-position of the chromene, or a mixture thereof in any ratio, including a racemic mixture.
  • reference to the “S isomer” of a compound refers to the compounds described herein in which the 2-position of the chromene is in the S configuration.
  • reference to the “R isomer” of a compound refers to the compounds described herein in which the 2-position of the chromene is in the R configuration.
  • deuterium in place of a hydrogen at one or more of the positions of Formula III are provided.
  • Formula III illustrates the 19 positions that can be deuterated. Carbon-hydrogen bonds that can be broken during metabolism: 1, 5, 6 (when R 3 is alkyl), 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19. Secondary deuterium isotope effects can be effected at positions 16, 17, 18 and 19.
  • Examples of compounds of Formula III include:
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III may have additional asymmetric carbon atoms, which may exist in various stereoisomeric forms. These various stereoisomeric forms are contemplated to be within the scope of the present disclosure.
  • Compounds of the present disclosure include diastereomerically or enantiomerically pure compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III. These diastereomerically or enantiomerically pure compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III provided herein may be prepared according to techniques known to those of skill in the art.
  • they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate or mixture of enantiomers or diastereomers by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer or diastereomer.
  • any conventional technique for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer or diastereomer.
  • a diastereomerically pure compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be obtained by reaction of the racemate or mix of diastereomers with a suitable optically active acid or base.
  • suitable acids or bases include those described in Bighley et al., 1995 , Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology , vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985 , Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973 , J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation , the contents of which are hereby incorporated by reference in their entireties.
  • Enantiomerically or diastereomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer or diastereomer used.
  • the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
  • the diastereoisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer or diastereomer regenerated by treatment with an appropriate base or acid.
  • the other enantiomer or diastereomer may be obtained from the racemate or mix of diastereomers in a similar manner or worked up from the liquors of the first separation.
  • an enantiomerically or diastereomerically pure compound can be separated from racemic compound or a mixture of diastereomers by chiral chromatography.
  • Various chiral columns and eluents for use in the separation of the enantiomers or diastereomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
  • Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to CHIRALPACK® IC, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., Synthetic Schemes below. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III that have been listed herein.
  • the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • intermediate A-7 for the synthesis of compounds of Formula I, Formula II, and Formula III can be synthesized from readily available functionalized azetidines A-1 and A-4.
  • Compound A-2 can be prepared by direct alkylation of A-1 or its O-protected analog using a suitably functionalized alkylating agent containing R 1 , such as LCH 2 R 1 under amine alkylation conditions, wherein L is a leaving group, such as halide (e.g., Br, Cl, I) or other leaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate, tresylate and the like.
  • R 1 such as LCH 2 R 1 under amine alkylation conditions
  • L is a leaving group, such as halide (e.g., Br, Cl, I) or other leaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate, tresylate and the like.
  • A-2 can be prepared by reductive amination of A-1 with HC(O)R 1 in the presence of hydrogen and a hydrogenation catalyst, such as Pt, Pd and the like.
  • A-2 is prepared by reacting XC(O)R 1 , where X is a leaving group, with A-4 under amide forming conditions to form the amidoketone A-5 followed by reduction of the resulting amidoketone A-5 using reducing agents known in the art, such as LAH and the like.
  • Nucleophilic aromatic substitution by A-2 of a halide on functionalized benzaldehyde A-3 by either aryl nucleophilic substitution (for fluoro-substituted A-3) or via Ullman coupling conditions (for iodo-substituted A-3) under conditions known in the art gives rise to intermediate A-7, wherein X is O.
  • the corresponding intermediate A-7 where X is S
  • the product thereof is reacted with a sulfide, such as sodium hydrogen sulfide and the like, to form the corresponding thiol.
  • the thiol is reacted with suitably functionalized alkylating agent containing R 1 , such as LCH 2 R 1 under amine alkylation conditions, wherein L is a leaving group, such as halide (e.g., Br, Cl, I) or another leaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate, tresylate and the like, and the resulting product is reacted with A-3 to form the A-7, where X is S.
  • R 1 such as LCH 2 R 1
  • L is a leaving group, such as halide (e.g., Br, Cl, I) or another leaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate, tresylate and the like
  • amidoketone A-5 can be coupled to ester A-6 via the phosphonium salt of A-5 in a Wittig reaction under Wittig forming conditions to form the alkene A-6.1.
  • Oxidation of the benzyl alcohol using oxidizing agents known in the art such as copper chromite; DMSO; Collins' reagent; Corey's reagent; pyridinium dichromate; sodium dichromate in water; and the like or DMSO, dicyclohexylcarbodiimide and anhydrous phosphoric acid under Moffatt oxidation conditions or anhydrous phosphoric acid and oxalyl chloride under Swern oxidation conditions and the like furnishes the aldehyde A-7, wherein X is CH 2 .
  • A-7 is an intermediate in the reaction in Scheme C, hereinbelow.
  • G 2 is defined as H, halogen, cyano or an oxygen-protecting group known in the art
  • one of G 4 and G 5 is H or halogen and the other is H, halogen or an oxygen-protecting group known in the art.
  • Chromanone B-6 is produced by treatment of B-3 with an iodobenzaldehyde B-5 under basic conditions using weak bases known in the art for such coupling reaction, such as piperidine, or DBU or similar bases in butanol or similar appropriate solvent.
  • the ketone moiety B-6 is converted to a tertiary alcohol by treatment with a source of methyl anion, such as treatment with methyl magnesium bromide or similar source followed by deprotection of G 2 , if G 2 is an oxygen protecting group, to give B-7.
  • the azetidine side chain is then introduced by treatment of B-7 with A-2 or the corresponding thiol under Ullmann reaction conditions using copper as a catalyst.
  • G 2 is defined as H, halogen, cyano or an oxygen-protecting group known in the art
  • one of G 4 and G 5 is H or halogen and the other is H, halogen or an oxygen-protecting group known in the art.
  • compounds of Formula I, Formula II, and Formula III may also be synthesized from compound B-3 by condensation with aldehyde A-7 under basic conditions such as piperidine, or DBU or similar bases in butanol or similar solvent to furnish C-1.
  • the ketone moiety of C-1 is then converted to a tertiary alcohol by treatment with a source of methyl anion such as treatment with methyl magnesium bromide or similar source to give C-2.
  • Elimination of the tertiary alcohol using acidic conditions known in the art and deprotection of protecting groups thereon then furnish previously described compound B-8 as a mixture of enantiomers.
  • G 2 is defined as H, halogen, cyano or an oxygen-protecting group known in the art, and one of G 4 and G 5 is H or halogen and the other is H, halogen or an oxygen-protecting group known in the art.
  • Scheme E exemplifies the preparation of compounds of the subject application where X is NH.
  • Intermediate E-1 is dissolved in butyronitrile (0.2 M).
  • the solution is degassed by passing a stream of nitrogen gas through it.
  • the mixture is heated at 125° C. for 0.5 to 2 h under inert atmosphere.
  • the mixture is allowed to cool to RT.
  • Ethyl acetate is added and insoluble materials removed by filtration through a pad of Celite®.
  • G 2 is defined as H, halogen, cyano or an oxygen-protecting group known in the art
  • one of G 4 and G 5 is H or halogen and the other is H, halogen or an oxygen-protecting group known in the art.
  • Chromanone F-5 is produced by treatment of F-3 with an 4-substituted benzaldehyde derivative F-4 (prepared by a Mitsunobu reaction as shown for A-7 where X ⁇ O in Scheme A) under basic conditions using weak bases known in the art for such coupling reaction, such as piperidine, or DBU or similar bases in butanol or similar appropriate solvent.
  • the ketone moiety F-5 is converted to a tertiary alcohol by treatment with a source of methyl anion, such as treatment with methyl magnesium bromide or similar source followed by deprotection of G 2 , if G 2 is an oxygen protecting group, to give F-6.
  • Scheme G illustrates how to prepare a compound of Formula I and Formula IA of the present invention wherein X is O.
  • a solution of 4-hydroxy-3,5-difluorophenylacetic acid (1 equiv.) and resorcinol (1.1 equiv.) in toluene (2 M) is purged with nitrogen and treated with boron trifluoride etherate (3 equiv.) added via addition funnel.
  • the resulting mixture is heated at 90° C. until all solids dissolved (1-5 h).
  • the mixture is then cooled to RT and quenched by slow addition of a saturated solution of sodium acetate.
  • the product is isolated as a solid or oil and may be used as is or purified with silica gel chromatography.
  • Condensation of G-3 with aldehyde G-4 is achieved by dissolving these materials in butanol (0.5 M) and treating the resulting solution with piperidine (0.3 equiv.) and diazabicyclo[5.4.0]undec-7-ene (0.3 equiv.).
  • the mixture is brought to reflux and water removed using a Dean-Stark apparatus. After removal of ca. one half of the starting butanol, the mixture is heated at reflux for an additional 1-4 h. The mixture is then allowed to cool to RT and 2-propanol (half the volume of butanol used) is added. A solid or gum may form. Alternatively, solvent and volatile materials are removed under reduced pressure to afford a gum.
  • Ketone G-5 is dissolved in tetrahydrofuran (0.3 M). The solution is cooled to 0° C. in an ice-bath. Methyl magnesium chloride (1.8 equiv.) is then added slowly to maintain a reaction temperature below 5° C. via syringe. After the addition is complete, the mixture is allowed to warm to RT and the reaction quenched by slow addition of saturated ammonium chloride. The product may precipitate as a gum or solid. Alternatively, the product may be isolated by extraction with ethyl acetate or other solvent.
  • 3-Azetidinone hydrochloride (10.000 g, 93.0 mmol, 1.0 equiv.), anhydrous 1,2-dichloroethane (200 mL) and diisopropylethylamine (38.9 mL, 223 mmol, 2.4 equiv.) were added to a round bottom flask (500 mL) to provide a light yellow suspension. The suspension was sonicated for 1 h and then cooled to ⁇ 10° C. (dry ice/MeOH) for 10 min. Propionyl chloride (9.8 mL, 112 mmol, 1.2 equiv.) was added dropwise to the cooled suspension to provide an orange solution.
  • Lithium aluminum hydride (10.397 g, 273.9 mmol, 3.0 equiv.) was suspended into THF (200 mL) and cooled in an ice-bath.
  • the flask was then fitted with a condenser and the reaction was heated at reflux in an oil bath at 75° C. for 16 h.
  • Lithium aluminum hydride (5.20 g, 140.7 mmol, 3.8 equiv.) was added to an ice cooled THF solution of methyl 4-((1-propionylazetidin-3-yl)methyl)benzoate (9.650 g, 36.9 mmol, 1.0 equiv.) in small portions.
  • the mixture was stirred at 0° C. for 10 min, then the mixture was evacuated and blanketed with nitrogen.
  • the greenish suspension was heated at 66° C. for 24 h. An aliquot was taken and worked up. NMR analysis of the aliquot indicated that the reaction was complete.
  • the reaction mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate.
  • the mixture was allowed to warm to RT and stirred for 10 min before being filtered through a pad of Celite®. After rinsing the Celite® pad with EA three times, the filtrate was concentrated to afford the title compound as a light yellow oil (7.18 g). The Celite® pad was rinsed with MeOH and the filtrate was concentrated. The residue was suspended in EA and filtered through a Celite® pad and rinsed with EA. The filtrate was concentrated to afford the title compound as a light yellow oil (0.87 g). The total yield was 8.05 g (99.4%). The material was used directly in the next step.
  • the resulting dark brown residue was purified on a silica gel column (12 g, 0-10% MeOH/DCM) to provide a dark oil that contained impure product.
  • the material was dissolved in acetonitrile and further purified on preparative HPLC (10-90% acetonitrile/H 2 O, 20 min) to provide the title compound as a light brown oil (0.073 g, 9.6%).
  • Step 1 Preparation of 2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • Step 2 Preparation of 4-methyl-2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-ol
  • Step 3 Preparation of 3-(4-hydroxyphenyl)-4-methyl-2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-2H-chromen-7-ol
  • the organic layer was separated and washed with sodium bicarbonate solution (1 time) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide a pinkish light brown solid.
  • the solid was purified on a silica gel column (24 g, 0-15% MeOH/DCM) to afford the title compound as a light yellow foam, which solidified on standing.
  • the solid was dried in a vacuum oven at 60° C. for 24 h to afford the title compound (0.12 g, 59.7%).
  • Solvent system 20% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Solvent system 20% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Step 1 Preparation of 2-(4-iodophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • the suspension was filtered and the solid washed with 25% diethyl ether/Hex to provide the title compound as a white powder (240.0 g, 54%).
  • the filtrate was concentrated and precipitation was performed, as above, to provide further compound (40.0 g, 9%).
  • the filtrates and the supernatant were combined, concentrated, adsorbed onto silica gel and purified on silica gel with 30% EA/Hex to provide the title compound as a yellow foam (137.0 g, 31%, m.p. 136-138° C.). Overall yield 94%.
  • Step 2 Preparation of 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-ol
  • Step 3 Preparation of 3-(4-hydroxyphenyl)-4-methyl-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2H-chromen-7-ol
  • the mixture was degassed and blanketed with argon (3 times). Copper(I) iodide (5.23 g, 27.5 mmol, 1.0 equiv.) was added to the degassed mixture. The mixture was further degassed and blanketed with argon an additional 3 times.
  • the reaction mixture was heated at 125° C. for 40 h. The reaction was cooled to ambient temperature and diluted with EA. The mixture was filtered through a pad of Celite®. The filtrate was washed with saturated aq. ammonium chloride (50 mL), water (50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The dark residue was cooled to ambient temperature and evacuated and blanketed with nitrogen.
  • the resulting residue was purified on a silica gel column (200 g, 0-15% MeOH/DCM gradient) to provide the title compound (6 g).
  • This material was further purified on a silica gel column (200 g, 0-15% MeOH/DCM, held at 6% MeOH/DCM).
  • the middle fractions were collected to afford the title compound (2 g).
  • the fractions containing impurities were collected and concentrated to provide a brown foam.
  • the brown foam was suspended in MeOH and sonicated.
  • the resulting solid was filtered and rinsed with MeOH. All batches were combined and analyzed by HPLC. The solid was dried in a vacuum oven at 60° C. overnight to afford the title compound as an off-white powder (3.64 g, 29%).
  • Solvent system 20% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Solvent system 20% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Step 1 Preparation of 2-(3-fluoro-4-((1-propylazetidin-3-yl)oxy)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • Step 2 Preparation of methyl 3-fluoro-4-((1-propionylazetidin-3-ylidene)methyl)benzoate
  • Step 3 Preparation of methyl 3-fluoro-4-((1-propionylazetidin-3-yl)methyl)benzoate
  • Step 6 Preparation of 2-(3-fluoro-4-((1-propylazetidin-3-yl)methyl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • the product was the major component, it was less polar than the aldehyde and the other spot was more polar than the aldehyde.
  • the reaction was cooled to RT and concentrated in vacuo at 30° C.
  • the resulting residue was dissolved in DCM and loaded onto a silica gel column and purified (40 g, 0-10% MeOH/DCM) to afford the title compound as a pale yellow foam (0.468 g, 36.8%).
  • Step 7 Preparation of 2-(3-fluoro-4-((1-propylazetidin-3-yl)methyl)phenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-chroman-4-ol
  • Step 8 Preparation of 2-(3-fluoro-4-((1-propylazetidin-3-yl)methyl)phenyl)-3-(4-hydroxyphenyl)-4-methyl-2H-chromen-7-ol
  • Solvent system 10% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Solvent system 10% denatured EtOH (90% EtOH, 5% IPA, 5% MeOH) in Hex with 0.1% DEA
  • Step 1 Preparation of ethyl 3-(2-fluoro-4,6-dimethoxyphenyl)-2-(4-methoxyphenyl)-3-oxopropanoate
  • 1-(2-Fluoro-4,6-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (2.770 g, 10.0 mmol, 1.0 equiv.) and pyridine hydrochloride (13.904 g, 120.3 mmol, 12.0 equiv.) were heated at 180° C. for 1 h under a stream of nitrogen. After cooling to RT, TLC showed starting material was still present. Additional pyridine hydrochloride (14 g) was added to the reaction and heated for another hour. TLC showed that additional product had formed but that starting material was still present. Additional pyridine hydrochloride (14 g) was added and allowed to react for 1 h. TLC showed much less starting material than product.
  • Step 4 Preparation of 1-(2-fluoro-6-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone
  • Step 5 Preparation of 5-fluoro-2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • the desired product was less polar than the aldehyde and the other spot was more polar than the aldehyde.
  • the reaction was cooled to RT and concentrated in vacuo at 30° C.
  • the resulting residue was dissolved in DCM and loaded onto a silica gel column and purified (40 g, 0-15% MeOH/DCM). Flash chromatography did not show any UV absorbance at any of the monitored wavelengths (220, 254, and 280 nm). Fractions with a yellow color were collected (120 mg, 35.7%) and LCMS indicated [M-18] + and [M-1THP] + . This material was used in the next reaction.
  • Step 6 Preparation of 5-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-2H-chromen-7-ol
  • Step 1 Preparation of 5-fluoro-2-(4-((1-propylazetidin-3-yl)methyl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one
  • Step 2 Preparation of 5-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2-chromen-7-ol
  • Resorcinol (1,3-dihydroxybenzene) (8.190 g, 74.4 mmol, 1.0 equiv.) and phenylacetic acid (10.430 g, 76.6 mmol, 1.0 equiv.) were added to a 250 mL round bottomed flask fitted with a stir bar and a condenser. Toluene (36.514 mL) was added to the flask to afford a suspension. Boron trifluoride etherate (26.182 mL, 208.5 mmol, 2.8 equiv.) was added through a syringe. The reaction was stirred and heated slowly to 100° C. The suspension became a light orange solution at 100° C.
  • the reaction was stirred at the same temperature for 2 h. TLC (30% EA/Hex) indicated the reaction was complete. The reaction was cooled to ambient temperature. A 12% aqueous solution of sodium acetate (0.645 g, 55 mL) was added dropwise to the reaction mixture and the reaction was stirred at RT for 2 h. The mixture was diluted with EA and the organic layer was washed with 12% sodium acetate aqueous solution (60 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated. The red oil was added to deionized water and heated at 70° C. for 30 min under nitrogen. The oil slowly solidified to afford a tan solid.
  • the mixture was cooled to ambient temperature and then to 0° C.
  • the solids were collected and rinsed with water.
  • the solids were dissolved in EA and dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was used directly in the next step without purification.
  • TLC (20% EA/Hex) indicated there were two equal amounts of products less polar than the starting material and starting material present.
  • DHP (8 mL) and a catalytic amount of pyridinium-toluenesulfonate were added at RT and the reaction was stirred for an additional 12 h.
  • TLC (20% EA/Hex) indicated that the reaction was complete.
  • TEA was added and the reaction mixture was concentrated to a brown residue. The residue was treated with MeOH and IPA but no solids were generated. The residue was dissolved in DCM and loaded onto a silica gel column (300 g, 0-20% EA/Hex). Fractions containing the product and small amounts of impurities were combined and concentrated. After concentration, the resulting residue was diluted with MeOH, the solid was filtered, and washed with MeOH to afford the title compound as a white solid (9 g). The filtrate was concentrated to afford additional product as a pale yellow solid (5 g).
  • Step 3 Preparation of 3-phenyl-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one
  • the flask was fitted with a Dean-Stark apparatus and condenser and heated in an oil bath at 130° C. Half the solvent (11 mL) was collected over 30 min. The reaction was heated for a further 12 h. LCMS indicated that the desired product was present. The reaction was concentrated and dissolved in DCM and loaded onto a silica gel column (25 g, 0-10% MeOH/DCM) to afford the title compound as a light brown foam. This material was used without further purification.
  • Step 4 Preparation of 4-methyl-3-phenyl-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2H-chromen-7-ol
  • the reaction mixture was concentrated and cooled to RT.
  • the reaction mixture was diluted with saturated aq. sodium bicarbonate, EA and stirred at RT for 30 min.
  • the mixture was separated.
  • the organic layer was washed with saturated aq. sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the resulting residue was dissolved in EA and loaded onto a silica gel column (25 g, 50% EA/Hex, 0-10% MeOH/DCM) and chromatographed to afford the title compound as an off-white foam. HPLC 94.4%.
  • reaction mixture was washed with saturated sodium bicarbonate (2 ⁇ 200 mL), brine (1 ⁇ 100 mL), dried over anhydrous Na 2 SO 4 , and concentrated to dryness.
  • the crude residue was adsorbed onto silica gel, and purified by flash chromatography. The column was eluted with MeOH (0 to 3%) in DCM to provide the title compound (8.97 g, 80%) as an off-white solid.
  • Step 2 Preparation of 2-(2-chloro-4-fluorophenyl)-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone
  • reaction mixture was washed with saturated sodium bicarbonate (2 ⁇ 100 mL), brine (1 ⁇ 100 mL), dried over anhydrous Na 2 SO 4 , and concentrated to dryness.
  • the crude residue was adsorbed on silica gel, and purified by flash chromatography.
  • the column was eluted with MeOH (0 to 2%) in DCM to provide 2-(2-chloro-4-fluorophenyl)-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone (4.34 g, 81%) as an off-white solid.
  • Step 3 Preparation of 3-(2-chloro-4-fluorophenyl)-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one
  • Step 4 Preparation of 3-(2-chloro-4-fluorophenyl)-4-methyl-2-(4-(1-propylazetidin-3-yl)oxy)phenyl)-2H-chromen-7-ol
  • Step 1 Preparation of 1-(2,4-dihydroxyphenyl)-2-(2-iso-propylphenyl)ethanone
  • the crude product was adsorbed on silica gel and purified by Combiflash column chromatography (40 g column, 0-5% MeOH/DCM) to provide 1-(2,4-dihydroxyphenyl)-2-(2-iso-propylphenyl)ethanone (470 mg, 47%) as a yellow solid.
  • Step 3 Preparation of 3-(2-iso-propylphenyl)-2-(4-((1-propylazetidin-3-yl)oxy)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one
  • a round-bottom flask containing 3-(2-iso-propylphenyl)-4-methyl-2-(4-(1-propylazetidin-3-yl)oxy)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-ol (66 mg, 0.1 mmol, 1.0 equiv.) was charged with an 80% aqueous solution of acetic acid (0.200 mL, 3.5 mmol, 30.3 equiv.) and water (0.800 mL, 44.4 mmol, 384.7 equiv.), and the resulting yellowish solution was purged with nitrogen and heated at 90° C. for 45 min under nitrogen.
  • a oven dried sealable flask was charged with anhydrous potassium carbonate (9.509 g, 68.8 mmol, 3.0 equiv.), 2-chlorophenylboronic acid (5.380 g, 34.4 mmol, 1.5 equiv.) and tetrakis-triphenylphosphine palladium (0) (1.325 g, 1.1 mmol, 0.1 equiv., 10 mol %) and 100 mL of toluene:EtOH (2:1) and stirred for 5 min at RT.
  • the reaction was stirred for 1 h. An aliquot of sample was taken and quenched with MeOH and Rochelle's salt solution and extracted with EA. TLC (10% EA/Hex) indicated the reaction was complete. The reaction was quenched with MeOH (0.5 mL) and diluted with DCM (30 mL) and stirred at ⁇ 78° C. for 10 min. Rochelle's salt solution was then added. The mixture was allowed to thaw and the phases were separated. The organic layer was washed with Rochelle's salt solution again, then brine, dried over anhydrous Na 2 SO 4 for 20 min. The colorless solution was passed through a DCM equilibrated silica gel plug. The filtrate was concentrated in vacuo at 6° C.
  • the oil was dissolved in DCM and transferred to a small round bottom flask (100 mL) and concentrated in vacuo. The resulting oil was dissolved in acetonitrile. The solution was frozen at ⁇ 78° C. and was placed on a lyopholizer overnight to afford the desired product as a viscous oil (0.32 g, 66%).
  • the resulting red residue was dissolved in DCM and silica gel ( ⁇ 1 g) was added and co-evaporated in vacuo.
  • the material was purified on a silica gel column (12 g, 0-10% MeOH/DCM).
  • the resulting red oil (280 mg) was taken up in THF (20 mL), and cooled to 0° C.
  • Concentrated HCl (0.500 mL, 6.0 mmol, 8.3 equiv.) was added to the above solution and the resulting mixture stirred at room temp. for 1.5 h.
  • the reaction was concentrated and sat'd NaHCO 3 solution (25 mL) and EA (25 mL) were added. The mixture was vigorously stirred at RT for 15 min.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or a pharmaceutically acceptable composition thereof to treat a disorder that is mediated, modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound with virtually no estrogenic effect.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can be administered in a pharmaceutical composition suitable for oral delivery to the patient, typically a human.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can be delivered in a carrier suitable for topical, transdermal (including by patch), intravenous, parenteral, intraaortal, subcutaneous or other desired delivery route, including any method of controlled delivery, for example, using degradable polymers, or with nano or microparticles, liposomes, layered tablets or other structural frameworks which slow delivery.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can be used to prevent a disorder modulated through the estrogen receptor, which comprises administering to a patient in need of such prevention, a prophylactically effective amount of a compound or pharmaceutical composition.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III can be in the form of a salt. It can be administered as a pharmaceutically acceptable salt, for example, a pharmaceutically acceptable acid addition salt, including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.
  • a pharmaceutically acceptable acid addition salt including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used to treat or prevent a disorder modulated by the estrogen receptor in an animal, typically a mammal, and most typically a human.
  • the present disclosure provides a combination of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt, and another pharmacologically active agent.
  • the selected compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can also be used as adjunctive therapy or combination therapy with another active agent (drug or other compound that has therapeutic or prophylactic properties).
  • a therapeutically effective amount of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can be used in combination with another anti-cancer agent, especially for estrogen receptor positive breast cancer, and in some embodiments, for estrogen receptor negative breast cancer.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA and Formula III or its pharmaceutically acceptable salt provided herein are administered for medical therapy in a therapeutically effective amount.
  • the amount of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound or salt administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions provided herein can be administered by a variety of routes including oral, topical, systemic, parenteral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal with a pharmaceutical carrier suitable for such administration.
  • a pharmaceutical carrier suitable for such administration.
  • the compound of one of the Formulas or its pharmaceutically acceptable salt is administered in a controlled release formulation.
  • Described herein below are various formulations comprised of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salts.
  • the formulation includes the active ingredient, as either a weight ratio or as a weight amount. It is to be understood, unless indicated to the contrary, that the weight amount and weight ratios are based upon the molecular weight of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III, even if the formulation contains the salt form thereof.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders.
  • the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt may be present as a minor component (as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • injectable compositions comprised of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salts are contemplated within the present disclosure.
  • injectable solutions use injectable carriers known within the art, such as injectable sterile saline or phosphate-buffered saline carriers and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt, for example in an amount ranging from about 0.01 to about 20% by weight, in another embodiment, from about 0.1 to about 20% by weight, in still another embodiment, from about 0.1 to about 10% by weight, and in still a different embodiment from about 0.5 to about 15% by weight.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt will typically be combined with either a suitable delivery polymeric composition, or a paraffinic or a water-miscible ointment base.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt may be formulated in a cream with, for example an oil-in-water cream base.
  • transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA and Formula III or its pharmaceutically acceptable salt can be administered by a transdermal device.
  • Transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. In certain embodiments, the formulation comprises hexapropyl- ⁇ -cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl- ⁇ -cyclodextrin (10-50% in water). In a more particular embodiment, the formulation comprises Captisol®.
  • the present disclosure also includes pharmaceutically acceptable acid addition salts of compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III.
  • the acids which are used to prepare the pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • formulation examples illustrate non-limiting representative pharmaceutical compositions that may be prepared in accordance with this disclosure for the purpose of illustration only.
  • the present invention is specifically not limited to the following pharmaceutical compositions.
  • the examples in the formulations hereinbelow refer to compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III, it is understood that the pharmaceutically acceptable salts thereof may be used in their stead.
  • the weight ratio is to be based upon the weight of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III present in the formulation without taking into account the weight attributable to the salt thereof.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
  • the mixture is filled into 250 mg capsules (125 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per capsule).
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III can be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III) in a tablet press. In other embodiments, there is between 10 and 500 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III in the oral tablet.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5, or 10, or 15, or 20, or 30 or 50 mg/mL
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets (5-1000 mg of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III per tablet) in a tablet press.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III described herein or its salt or pharmaceutically acceptable composition as described herein are complete anti-estrogens useful to treat any disorder modulated, mediated or affected by the estrogen receptor.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used in combination or alternation with another anti-cancer agent for the treatment of cancer, as described more fully below.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used in combination or alternation with estrogen or a partial estrogen receptor antagonist for the treatment of a postmenopausal disorder, also described below.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used to treat local, advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer).
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used to treat estrogen or progesterone receptor negative breast cancer.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, either by itself or in combination with one or more other anti-cancer agents described below or otherwise known to those skilled in the art. It is also useful for second line therapy for treatment after a previous hormonal therapy has failed, either by itself or in combination with another anticancer agent, for example, a targeted therapy such as an mTOR inhibitor such as everolimus
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III or their pharmaceutically acceptable salts are also useful as adjunctive therapy after or instead of chemotherapy, radiation or surgery. Such adjuvant use is often used for several years, perhaps 5 years, after chemotherapy or other therapies have been concluded, but may optimally be continued for additional years.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III or their pharmaceutically acceptable salts are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely.
  • a patient typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRACA1 or BRACA2 gene or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence.
  • these compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts also are useful in treating other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts or compositions thereof can be used in conjunction with selective estrogen receptor modulators (SERMS) referred to herein and together they are useful for hormonal therapy for postmenopausal women in particular to treat or prevent osteoporosis.
  • SERMS selective estrogen receptor modulators
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt is used in combination with an estrogen, SERM or partial anti-estrogen whereby the complete anti-estrogen prevents adverse action of the total or partial estrogen on the uterus and other tissues.
  • the present compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III and their pharmaceutically acceptable salts are used as therapeutic or prophylactic agents for the treatment of conditions in mammals, particularly humans that are modulated by estrogen receptors.
  • An oral pharmaceutical composition comprised of a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salts thereof are useful for treating locally advanced or metastatic breast cancer, preventing recurrence or early breast cancer after surgery, and preventing breast cancer in women at high risk. They are also useful for treating all estrogen-dependent cancers of the reproductive tract including endometrial and ovarian cancers. They can be used in the treatment of lung and bronchial cancers that express estrogen receptors.
  • Selective estrogen receptor modulators such as tamoxifen, raloxifene, lasofoxifene, and apeledoxifene additionally have application as hormone replacement therapy to prevent osteoporosis and other disorders such as hot flashes, etc. in post-menopausal women, a use that depends on their partial estrogen like action, for example, on bone.
  • the compound of Formula I, Formula IA, Formula II, Formula IIA and Formula III or its pharmaceutically acceptable salts described herein can be employed in combination with an estrogen or a selective estrogen receptor modulator to block the unwanted estrogenic activity of the therapy.
  • the complete anti-estrogen is dosed in the amount to prevent the adverse action of the estrogen or estrogen receptor modulator on the uterus and mammary gland yet allowing the beneficial action of estrogen on bone and vasomotor symptoms.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts can be administered for the treatment of cancer, and in particular breast cancer in combination or association with Herceptin, Tykerb, CDK4/6 inhibitor such as PD-0332991, mTOR inhibitor such as Novartis' everolimus and other rapamycin analogs such as rapamycin and temsirolimus, Millennium's MLN0128 TORC1/2 inhibitor, an EFGR-family inhibitor such as trastuzumab, pertuzumab, ado-trastuzumab emtansine, erlotinib, gefitinib, neratinib and similar compounds, a PI3 Kinase Inhibitor such as perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145, a histone deacetylase inhibitor such as vorinostat, romidepsin
  • provided herein is a method of treating a mammal susceptible to or afflicted with a condition influenced by estrogen receptor by administering to a subject in need thereof a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt thereof.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts are provided for use in medical therapy, including for any of the conditions described herein.
  • the use of the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases is also contemplated to be within the purview of this disclosure.
  • Injection dose levels of injectable solutions comprised of compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III or their pharmaceutically acceptable salts are provided in any desired dosage, for example, from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more comprised of the compounds of Formula I, Formula IA, Formula II, Formula IIA or Formula III or their pharmaceutically acceptable salts may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • any dose is appropriate that achieves the desired goals.
  • suitable daily dosages are between about 0.1-4000 mg, more typically between 5 mg and 1 gram, more typically between 10 mg and 500 mg, and administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g., 3-5 days a week).
  • the dose of the compounds of Formula I or their pharmaceutically acceptable salts usually range between about 0.1 mg, more usually 10, 50, 100, 200, 250, 1000 or up to about 2000 mg per day.
  • the regimen for treatment usually stretches over many months or years. Oral dosing may be preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, nonlimiting dosages might range from about 0.01 to about 20 mg/kg of the compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salt provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts When used to prevent the onset of cancer, a neurodegenerative, autoimmune or inflammatory condition, the compounds of Formula I, Formula IA, Formula II, Formula IIA and Formula III or their pharmaceutically acceptable salts will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of Formula I, Formula IA, Formula II, Formula IIA or Formula III or its pharmaceutically acceptable salts provided herein can be administered as the sole active agent or it can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • Proliferation of MCF-7 breast cancer cells was measured using a fluorescent DNA binding dye 6-8 days after treatment in triplicate with representative compounds in the presence of 100 pM E2 in hormone-depleted medium. IC 50 's were calculated from individual experiments as in Example 25.
  • ER ⁇ expression was detected in MCF-7 cell lysates treated with 100 nM antiestrogens in serum-free medium for 24 hours and immunoblotted with an antibody specific to ER ⁇ . Band intensity was normalized relative to vehicle for each individual experiment and listed in Table 3 (Relative change ER ⁇ levels (% vehicle)).
  • ECC-1 cells American Type Culture Collection, Manassas, Va.
  • RPMI medium 10% fetal bovine serum at 37° C.
  • trypsinized cells were resuspended in RPMI medium plus 5% charcoal dextran stripped serum (CDSS, (Hyclone, Logan, Utah)) and plated at a density of 25-50 k cells per well into a 96-well plate for at least 6 hours.
  • Representative compounds were diluted in serum-free medium and added 1:1 to plated cells in replicate wells (2.5% CDSS final). Plates were incubated for 3 days at 37° C. and subsequently frozen at ⁇ 80° C.
  • AP activity was normalized to 500 pM 17 ⁇ -estradiol (E2), reported as the maximum activity observed for each individual experiment, regardless of dose. This assay was shown to correlate with the in vivo studies comparing uterine wet weight in ovariectomized rats following treatment with a number of anti-estrogens. The assay results for induction of AP activity in uterine cells (% E2) are listed in Table 4.
  • AP activity was assayed as in Example 28 but cells were co-treated with 500 pM E2.
  • the assay results are listed in Table 5.

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WO2016174551A1 (en) 2016-11-03
UY36651A (es) 2016-11-30

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